Fate of tritiated didemnin B in mice: excretion and tissue concentrations after an intraperitoneal dose

Beasley, Val R.; Bruno, Sally J.; Burner, John S.; Choi, Byoung Wook; Rinehart, Kenneth L.; Koritz, G. D.; Levengood, Jeffrey M.

doi:10.1002/bdd.466

Cited by 8 publications

(13 citation statements)

References 30 publications

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“…The terminal half-life of HHT has been determined to be 14.4 hrs in human [54] and 40.6 hrs in dogs [55]. The clearance of Did B from the blood of human patients is biphasic with apparent half-lives of 0.12 and 4.8 hrs [56] and its observed terminal half-life in mice is 16.2 hrs [57]. The elimination half-life of Bru in mice has been estimated to be greater than 12 hrs and in human serum it is biphasic and progresses through an initial fast half-life of 15 min followed by a second half-life of 0.7–13.8 hrs depending on the patients [58].…”

Section: Discussionmentioning

confidence: 99%

Altering Chemosensitivity by Modulating Translation Elongation

et al. 2009

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BackgroundThe process of translation occurs at a nexus point downstream of a number of signal pathways and developmental processes. Modeling activation of the PTEN/AKT/mTOR pathway in the Eμ-Myc mouse is a valuable tool to study tumor genotype/chemosensitivity relationships in vivo. In this model, blocking translation initiation with silvestrol, an inhibitor of the ribosome recruitment step has been showed to modulate the sensitivity of the tumors to the effect of standard chemotherapy. However, inhibitors of translation elongation have been tested as potential anti-cancer therapeutic agents in vitro, but have not been extensively tested in genetically well-defined mouse tumor models or for potential synergy with standard of care agents.Methodology/Principal FindingsHere, we chose four structurally different chemical inhibitors of translation elongation: homoharringtonine, bruceantin, didemnin B and cycloheximide, and tested their ability to alter the chemoresistance of Eμ-myc lymphomas harbouring lesions in Pten, Tsc2, Bcl-2, or eIF4E. We show that in some genetic settings, translation elongation inhibitors are able to synergize with doxorubicin by reinstating an apoptotic program in tumor cells. We attribute this effect to a reduction in levels of pro-oncogenic or pro-survival proteins having short half-lives, like Mcl-1, cyclin D1 or c-Myc. Using lymphomas cells grown ex vivo we reproduced the synergy observed in mice between chemotherapy and elongation inhibition and show that this is reversed by blocking protein degradation with a proteasome inhibitor.Conclusion/SignificanceOur results indicate that depleting short-lived pro-survival factors by inhibiting their synthesis could achieve a therapeutic response in tumors harboring PTEN/AKT/mTOR pathway mutations.

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Section: Discussionmentioning

confidence: 99%

Altering Chemosensitivity by Modulating Translation Elongation

et al. 2009

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“…administration (Beasley et al. ), we examined gross pancreatic and islet morphology by insulin staining and light microscopy (Fig. A).…”

Section: Resultsmentioning

confidence: 99%

“…delivery (Beasley et al. ). Both the intestine and pancreas are known sites of production of the orexigenic peptide, ghrelin, with the intestine being the more important source in mice (Wierup et al.…”

Section: Discussionmentioning

confidence: 99%

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Treatment with didemnin B, an elongation factor 1A inhibitor, improves hepatic lipotoxicity in obese mice

et al. 2016

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Eukaryotic elongation factor EEF1A1 is induced by oxidative and ER stress, and contributes to subsequent cell death in many cell types, including hepatocytes. We recently showed that blocking the protein synthesis activity of EEF1A1 with the peptide inhibitor, didemnin B, decreases saturated fatty acid overload‐induced cell death in HepG2 cells. In light of this and other recent work suggesting that limiting protein synthesis may be beneficial in treating ER stress‐related disease, we hypothesized that acute intervention with didemnin B would decrease hepatic ER stress and lipotoxicity in obese mice with nonalcoholic fatty liver disease (NAFLD). Hyperphagic male ob/ob mice were fed semipurified diet for 4 weeks, and during week 5 received i.p. injections of didemnin B or vehicle on days 1, 4, and 7. Interestingly, we observed that administration of this compound modestly decreased food intake without evidence of illness or distress, and thus included an additional control group matched for food consumption with didemnin B‐treated animals. Treatment with didemnin B improved several characteristics of hepatic lipotoxicity to a greater extent than the effects of caloric restriction alone, including hepatic steatosis, and some hepatic markers of ER stress and inflammation (GRP78, Xbp1s, and Mcp1). Plasma lipid and lipoprotein profiles and histopathological measures of NAFLD, including lobular inflammation, and total NAFLD activity score were also improved by didemnin B. These data indicate that acute intervention with the EEF1A inhibitor, didemnin B, improves hepatic lipotoxicity in obese mice with NAFLD through mechanisms not entirely dependent on decreased food intake, suggesting a potential therapeutic strategy for this ER stress‐related disease.

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“…Beasley and colleagues (45) completed a study of the excretion and tissue concentrations of [ 3 H] didemnin B in mice after intraperitoneal administration. Interestingly, they found that the pancreas had the greatest concentration of radiolabel at both the high and low doses 7 days after administration, which suggested possible efficacy in animal models for the treatment of pancreatic cancer.…”

Section: -6 Antitumour Pharmacology Of Marine Natural Products Wimentioning

confidence: 99%

Marine pharmacology in 2005–2006: Antitumour and cytotoxic compounds

Mayer

Gustafson

2008

European Journal of Cancer

121

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During 2005 and 2006, marine pharmacology research directed towards the discovery and development of novel antitumour agents was reported in 171 peer-reviewed articles. The purpose of this article is to present a structured review of the antitumour and cytotoxic properties of 136 marine natural products, many of which are novel compounds that belong to diverse structural classes, including polyketides, terpenes, steroids, and peptides. The organisms yielding these bioactive marine compounds included invertebrate animals, algae, fungi and bacteria. Antitumour pharmacological studies were conducted with 42 structurally defined marine natural products in a number of experimental and clinical models which further defined their mechanisms of action. Particularly potent in vitro cytotoxicity data generated with murine and human tumour cell lines was reported for 94 novel marine chemicals with as yet undetermined mechanisms of action. Noteworthy is the fact that marine anticancer research was sustained by a global collaborative effort, involving researchers from Australia, Belgium, Benin, Brazil, Canada, China, Egypt, France, Germany, India, Indonesia, Italy, Japan, Mexico, the Netherlands, New Zealand, Panama, the Philippines, Slovenia, South Korea, Spain, Sweden, Taiwan, Thailand, United Kingdom, and the United States. Finally, this 2005-6 overview of the marine pharmacology literature highlights the fact that the discovery of novel marine antitumour agents continued at the same active pace as during 1998-2004.

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Fate of tritiated didemnin B in mice: excretion and tissue concentrations after an intraperitoneal dose

Cited by 8 publications

References 30 publications

Altering Chemosensitivity by Modulating Translation Elongation

Altering Chemosensitivity by Modulating Translation Elongation

Treatment with didemnin B, an elongation factor 1A inhibitor, improves hepatic lipotoxicity in obese mice

Marine pharmacology in 2005–2006: Antitumour and cytotoxic compounds

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